The present invention is generally directed to cardiac therapy, and more particularly to ameliorating, preventing, and/or reversing arrhythmic risk associated with cardiomyopathy.
Despite extensive research and novel treatments, conditions associated with deranged cardiac metabolism, such as heart failure or ischemia, are still accompanied by a substantial risk of arrhythmic sudden death (Reference 1). While implanted cardiac defibrillators have decreased sudden death risk, they can cause physical and psychological complications. They are also expensive, and do not address the underlying pathology that leads to arrhythmic risk (References 2-3). A more complete molecular understanding of the basis for the increased arrhythmic risk is likely to lead to new therapies that will be more effective and less invasive.
Cardiac injury from many causes is associated with altered metabolism and downregulation of the cardiac Na+ channel (Nav 1.5) (References 4-7). Recently, we reported that an elevation of intracellular reduced nicotinamide adenine dinucleotide (NADH) can downregulate Na+ current (INa) acutely and to a degree that is large enough to be clinically significant (Reference 8). The signaling cascade involves a protein kinase C (PKC)-mediated increase in mitochondrial reactive oxygen species (ROS) production (References 9-10). NADH is known to oscillate with myocardial ischemia, and mitochondrial injury is associated with increased NADH and ROS levels (References 11-12). These changes could contribute to reduced INa, conduction block, and arrhythmic risk known to exist with reduced cardiac contractility. The NADH effect on ROS production and INa can be antagonized by PKA activation mediated by NAD+, by superoxide dismutase, or by 2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), a scavenger of mitochondrial ROS (References 9-10).
In this study, we tested whether NADH and mitochondrial ROS were elevated in nonischemic cardiomyopathy and whether these changes resulted in a reduction in INa. We also investigated whether NAD+ and 2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) could counteract the effects of NADH on mitochondrial ROS and cardiac INa in nonischemic cardiomyopathy. The PKC inhibitor chelerythrine and PKA activator forskolin were utilized to test whether they participated in the signaling pathway of NADH/NAD+ modification of the Nav 1.5 of DOCA myocytes.